Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt.
Lipids Health Dis. 2022 Aug 4;21(1):67. doi: 10.1186/s12944-022-01678-y.
Inflammatory breast cancer (IBC) represents a deadly aggressive phenotype of breast cancer (BC) with a unique clinicopathological presentation and low survival rate. In fact, obesity represents an important risk factor for BC. Although several studies have identified different cellular-derived and molecular factors involved in IBC progression, the role of adipocytes remains unclear. Cancer-associated adipose tissue (CAAT) expresses a variety of adipokines, which contribute to tumorigenesis and the regulation of cancer stem cell (CSC). This research investigated the potential effect of the secretome of CAAT explants from patients with BC on the progression and metastasis of the disease.
This study established an ex-vivo culture of CAAT excised from IBC (n = 13) vs. non-IBC (n = 31) patients with obesity and profiled their secretome using a cytokine antibody array. Furthermore, the quantitative PCR (qPCR) methodology was used to validate the levels of predominant cytokines at the transcript level after culture in a medium conditioned by CAAT. Moreover, the impact of the CAAT secretome on the expression of epithelial-mesenchymal transition (EMT) and cells with stem cell (CSC) markers was studied in the non-IBC MDA-MB-231 and the IBC SUM-149 cell lines. The statistical differences between variables were evaluated using the chi-squared test and unpaired a Student's t-test.
The results of cytokine array profiling revealed an overall significantly higher level of a panel of 28 cytokines secreted by the CAAT ex-vivo culture from IBC patients with obesity compared to those with non-IBC. Of note, interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemo-attractant protein 1 (MCP-1) were the major adipokines secreted by the CAAT IBC patients with obesity. Moreover, the qPCR results indicated a significant upregulation of the IL-6, IL-8, and MCP-1 mRNAs in CAAT ex-vivo culture of patients with IBC vs. those with non-IBC. Intriguingly, a qPCR data analysis showed that the CAAT secretome secretions from patients with non-IBC downregulated the mRNA levels of the CD24 CSC marker and of the epithelial marker E-cadherin in the non-IBC cell line. By contrast, E-cadherin was upregulated in the SUM-149 cell.
This study identified the overexpression of IL-6, IL-8, and MCP-1 as prognostic markers of CAAT from patients with IBC but not from those with non-IBC ; moreover, their upregulation might be associated with IBC aggressiveness via the regulation of CSC and EMT markers. This study proposed that targeting IL-6, IL-8, and MCP-1 may represent a therapeutic option that should be considered in the treatment of patients with IBC.
炎性乳腺癌（IBC）是一种具有独特临床病理表现和低生存率的致命侵袭性乳腺癌（BC）表型。事实上，肥胖是 BC 的一个重要危险因素。尽管有几项研究已经确定了与 IBC 进展相关的不同细胞衍生和分子因素，但脂肪细胞的作用仍不清楚。癌相关脂肪组织（CAAT）表达多种脂肪因子，这些脂肪因子有助于肿瘤发生和癌症干细胞（CSC）的调节。本研究旨在研究来自肥胖的 IBC（n=13）和非 IBC（n=31）患者的 CAAT 外植体的分泌组对疾病进展和转移的潜在影响。
本研究建立了 IBC（n=13）与非 IBC（n=31）肥胖患者的 CAAT 体外培养物，并使用细胞因子抗体阵列对其分泌组进行了分析。此外，还使用定量 PCR（qPCR）方法在 CAAT 条件培养基中培养后，在转录水平上验证主要细胞因子的水平。此外，还研究了 CAAT 分泌组对非 IBC MDA-MB-231 和 IBC SUM-149 细胞系中上皮-间充质转化（EMT）和具有干细胞（CSC）标志物的细胞表达的影响。使用卡方检验和未配对学生 t 检验评估变量之间的统计差异。
细胞因子阵列分析结果显示，与非 IBC 患者相比，来自肥胖的 IBC 患者的 CAAT 体外培养物中一组 28 种细胞因子的总体水平显著升高。值得注意的是，白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和单核细胞趋化蛋白 1（MCP-1）是肥胖的 IBC 患者 CAAT 分泌的主要脂肪因子。此外，qPCR 结果表明，IBC 患者 CAAT 体外培养物中 IL-6、IL-8 和 MCP-1 的 mRNA 水平显著上调。有趣的是，qPCR 数据分析显示，非 IBC 患者的 CAAT 分泌组分泌物下调了非 IBC 细胞系中 CD24 CSC 标志物和上皮标志物 E-钙粘蛋白的 mRNA 水平。相比之下，SUM-149 细胞中的 E-钙粘蛋白上调。
本研究确定了来自 IBC 患者而不是非 IBC 患者的 CAAT 中 IL-6、IL-8 和 MCP-1 的过表达作为预后标志物；此外，它们的上调可能通过调节 CSC 和 EMT 标志物与 IBC 的侵袭性有关。本研究提出靶向 IL-6、IL-8 和 MCP-1 可能是治疗 IBC 患者的一种治疗选择。
